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COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, factors associated with this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we find that baseline expression of AP-1 transcription factors, FOS and ATF3, is inversely correlated with BNT162b2 mRNA vaccine-induced T-cell responses. FOS expression is associated with transcription modules related to baseline immunity, but it is negatively associated with those related to T-cell activation upon BNT162b2 mRNA stimulation. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with FOS and ATF3 expression and inversely correlated with BNT162b2-induced T-cell responses. Taken together, these results demonstrate that baseline expression of AP-1 genes, which is associated with the gut microbial fucose/rhamnose degradation pathway, is a key negative correlate of BNT162b2-induced T-cell responses.

Immunomodulatory function of all-trans retinoic acid (ATRA) has been gathering much attention for the therapy of autoimmune diseases. ATRA is a chemically unstable molecule which requires proper formulation for targeted delivery. Here we examined nanostructured lipid carrier (NLC) for the formulation of ATRA. NLC is a representative nanoparticle formulation especially suited for oral delivery. We established the preparation procedures of ATRA-containing NLC (NLC-RA) which minimizes the degradation of ATRA during the preparation process. NLC-RA thus obtained was taken up by macrophages and induced anti-inflammatory response via suppressing NF-κB signaling as well as via enhancing the production of anti-inflammatory cytokines. Moreover, NLC-RA enhanced differentiation of naïve T cells to regulatory T cells in the co-culture system with dendritic cells. These results suggest that NLC-RA is a promising alternative therapy for the autoimmune diseases especially intestinal bowel disease.

The active form of vitamin D3, 1,25(OH)2D3 has been found to exert multiple effects on the suppression of progression of inflammatory bowel disease (IBD). Vitamin D3 has been gathering attention as a therapy for IBD. However, the clinical trials conducted to date revealed that a relatively high dosage of vitamin D3 was required to see a significant therapeutic effect. Thus, effective formulation and delivery of vitamin D3 to colonic inflammatory lesions will be required. Herein we describe the preparation of a nanostructured lipid carrier (NLC) for the encapsulation of 1,25(OH)2D3 for colonic delivery via oral administration. The optimized fabrication procedure enabled the incorporation of 1,25(OH)2D3 in the NLC by minimizing the destruction of chemically unstable 1,25(OH)2D3. The obtained NLCs orally delivered 1,25(OH)2D3 to the colon in mice and maintained a high concentration of 1,25(OH)2D3 in the colonic tissue for at least 12 h. The NLC showed multiple effects on the suppression of symptoms of colitis induced by dextran sodium sulfate, namely maintaining crypt structure, reducing the tissue concentration of inflammatory cytokines, suppressing the infiltration of polymorphonuclear leukocytes, and augmenting anti-inflammatory CX3CR1high macrophages. Our NLCs containing 1,25(OH)2D3 may be an alternative treatment for IBD therapy.

Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alpha-mannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of N-glycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophil-attracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.Key words: inflammatory bowel disease, alpha-mannosidase II, intestinal epithelial cell, N-glycosylation.

The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases (IBDs); however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin not only establishes a first-line barrier against pathogens, but also serves as a niche for microbial growth. We hypothesized that dysbiosis may cause abnormal mucin utilization and microbial metabolic dysfunction. To test this hypothesis, we analyzed short-chain fatty acids (SCFAs) and mucin components in the stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn’s disease (CD) patients from Japan. The levels of n-butyrate were significantly lower in the stools of both the CD and UC patients than in those of the healthy subjects. Correlation analysis identified 7 bacterial species positively correlated with n-butyrate levels, among which the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans act as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in the colonic lamina propria. Importantly, the availability of mucin-associated O-glycans to the microbiota was significantly reduced in n-butyrate-deficient UC patients. Taken together, our findings highlight the biological significance of the symbiosynthesis pathway in the production of n-butyrate, which maintains gut immune homeostasis.

Background: The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases (IBDs); however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin not only establishes a first-line barrier against pathogens, but also serves as a niche for microbial growth. Methods: To elucidate relationships between dysbiosis, abnormal mucin utilization, and microbial metabolic dysfunction, we analyzed short-chain fatty acids (SCFAs) and mucin components in the stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn's disease (CD) patients from Japan. Findings: The levels of n-butyrate were significantly lower in the stools of both the CD and UC patients than in those of the healthy subjects. Correlation analysis identified 7 bacterial species positively correlated withn-butyrate levels, among which the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans act as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in the colonic lamina propria. Importantly, the availability of mucin-associated O-glycans to the microbiota was significantly reduced inn-butyrate-deficient UC patients. Interpretation: Our findings demonstrated that mucin O-glycans facilitate symbiosynthesis of n-butyrate by gut microbiota. Abnormality in the mucin utilization may lead to decreased n-butyrate production in UC patients. Funding Statement: This study was supported by grants from the Japan Society for the Promotion of Science (#16H01369, 17KT0055, and 18H04680 to KH), Health Labour Sciences Research Grant (KH and JK), AMED-Crest (#16gm0000000h0101, 17gm1010004h0102, and 18gm1010004h0103 to KH and JK), AMED (#18ek0109303h0001 to KH and JK), Yakult Foundation (KH), Keio Gijuku Academic Development Funds (KH), The Aashi Grass Foundation, and The Canon Foundation (JK). Declaration of Interests:The authors have declared that no competing interests exist. Ethics Approval Statement: The protocol was approved by the ethics committees of Osaka University (#13165-2), The University of Tokyo (#25-42-1122), Keio University (#150421-1), Shizuoka University (#14-11), and NIBIOHN (#72) prior to subject inclusion. All animal experiments were performed according to protocols approved by the Animal Use Committees of Keio University and Shizuoka University. The rats and mice were maintained in accordance with the guidelines for the care of laboratory animals of Shizuoka University and Keio University, respectively.

Summary Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer’s patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.

The active form of vitamin D

To compensate the large irreversible capacity (Qirr), lithium was pre-doped to Si thin flakes (Si Leaf Powder® (Si-LP), thickness: 100 nm) for different times, and its effects on the charge/discharge characteristics such as reversible capacity, cycleability, and rate-capability were investigated in detail. The charge/discharge test results showed that a large initial Qirr of ca. 2300 mAh g− 1 for the Si-LP can be completely compensated by Li pre-doping, and a high capacity (> 2500 mAh g− 1) was obtained for pre-doped Si-LPs. The pre-doping did not cause any harmful effects on cycleability as long as lithium was uniformly pre-doped. The addition of vinylene carbonate to the electrolyte solution in the pre-doping and in the test cell greatly improved the cycleability, and a high discharge capacity of ca. 2300 mAh g− 1 was kept after 40 cycles.

Geometrical relationships and interactions among hierarchical structures in homogeneous isotropic turbulence are investigated by identifying individual vortices of three different scales in the inertial subrange. Fourier bandpass filters are employed to extract the vortices, and each extracted vortex is replaced by a group of vortex segments with a cylindrical shape. The axes of neighboring vortices tend to be anti-parallel when the distance between them is equivalent to their diameter. Further, results indicate that a vortex is most strongly stretched by vortices twice the scale irrespective of the Reynolds number and the vortex scales. Then, the geometric relationships between the vortices being stretched and those that cause the stretching are analyzed, and the stretching is found to be particularly strong when the two vortices are orthogonal to each other.

A wind tunnel experiment was performed to investigate the suitable conditions in which a localized turbulent region can easily be generated in a flat-plate boundary layer. An artificial disturbance of zero-mass flux was introduced upstream using a combination of a short-duration jet and suctions to prepare a potentially unstable environment. The disturbed region by itself decayed downstream. Another jet was then ejected downstream at several different timings and two different spanwise locations relative to the passage of the locally disturbed region to promote transition to turbulence. Although the jet was too weak to trigger the turbulence transition by itself, an isolated turbulent region, the so-called turbulent spot, was generated when ejected against the disturbed region. The optimum conditions were found when the jet was ejected between the high- and low-speed areas of the convecting unstable region.

Pure Si thin flakes (Si Leaf Powder® (Si-LP)) of different thicknesses (50, 100, 200, 300 and 400 nm) were prepared, and their charge/discharge properties were investigated as negative electrode materials for lithium ion batteries (LIBs). High reversible capacity (2200–2500 mAh g − 1 ) and good capacity retention were obtained for thinner Si-LPs (50–200 nm), while thicker samples (300 and 400 nm) exhibited rapid capacity fade upon cycling at C/6. For the thinner flakes, agglomeration and large cracks were confirmed on the composite electrodes, but no pulverization of the flakes was observed. These data suggested that Li atoms diffused easily within the thinner Si-LPs and the uniformity of Li distribution suppressed the localized physical stress that caused by alloying and de-alloying. In addition, the addition of vinylene carbonate (VC) in the electrolyte was found to be quite effective for improving not only the cycleability, but also the rate-capability. The best performance was obtained for Si-LP (100 nm), which exhibited a superior cycleability (ca. 2300 mAh g − 1 at C/6 after 50 cycles) and a high rate capability (ca. 1400 mAh g − 1 at 12 C rate).

Stretching vortices whose sizes are in the inertial subrange of a homogeneous isotropic turbulence are picked up, and the geometric relations with the neighboring vortices whose scales are twice larger are studied. Hierarchical vortices are extracted using a Fourier band-pass filter, and each extracted vortex is reconstructed as a set of short cylindrical segments along the vortex axis to discuss the vortex interactions. As a result, it is shown that the directions of larger vortices near the segments of the fast stretching vortices tend to be orthogonal to the direction of the stretching segments, and the locations of the larger vortices that contribute most to the stretching of smaller vortex segments are likely to be found in the direction with the relative angle of 45° from the axes of the stretching vortex segments. And, the vortices with the second highest contributions tend to be in the directions 45° from the stretching segments' axes and orthogonal to the directions of the highest contributing vortices.

Li-Si alloy is a promising high capacity anode; however, the poor cycleability should be improved for commercial applications. The poor cycleability has been attributed to a large volume during the charge/discharge cycling, resulting fracture and pulverization of Si particles. Therefore, relaxation of the physical stress is important to attain a good cycleability. It has been well recognized that Si nano-particles effectively reduces the stress by the expansion and shrinkage, which gives a good cycleability. However, the use of nano-particles results in a low packing density of the electrode. We designed Si nano-flakes called Si Leaf-Powder®(LP), which enables us to reduce the stress by the expansion and shrinkage and to make highly dense electrode composites. We prepared Si nano-flakes of different thickness (50-400 nm, Fig. 1) by a vapor phase deposition, and have investigated their charge and discharge characteristics [1-3]. Here we discuss the cycleability, the irreversible capacity, and the surface film (SEI) growth during cycling of the Si nano-flakes. The cycleability of Si-LPs of different thicknesses at C/6 in 1 M LiPF6/EC+DEC(1:1) +10 wt% VC is shown in Fig. 2 [1]. The cycleability of Si-LPs greatly depended on the thickness. Thinner samples (50-200 nm) showed relatively good cycleability, while thicker samples (300 and 400 nm) showed poor cycleability. For the thinner samples, the diffusion of metallic Li in the Si flakes is facile. The resulting uniform distribution of Li within the nano-flake during charging and discharging suppressed the physical stress and resulted in good cycleability. The large irreversible capacity (Q irr) of Si anodes is a serious problem for use in practical lithium-ion cells. The addition of VC does not reduce Q irr. The origin of the large Q irr has been attributed to the reduction of surface SiOx and solvent decomposition (and the following SEI formation), but such an extremely large Q irr of > 1000 mAh g-1is most probably owing to the latter phenomenon. We found that coating of Si-LPs with thin carbon layer is effective for reducing Q irr [2]. However, crack formation of the carbon layer decreased the Coulombic efficiency the initial cycles, and we concluded that further remarkable reduction of Q irr cannot be expected. To reduce Q irr, we also found that a pre-doping technique is effective. We can reduce Q irr practically to zero by the pre-doping technique, and we obtained good cycleability similar to that without pre-doping [3]. Figure 3 shows the variations of the discharge capacity and Coulombic efficiency of Si-LP (100 nm) upon a long-term cycle test. The Si-LP sample showed good cycleability up to the 500th cycle. The initial capacity was ca. 2000 mAh g-1, and gradually decreased to ca. 1500 mAh g-1at the 500 cycle. Unfortunately, the capacity suddenly dropped after the 560 cycle, the reason of which is not clear at present. Though Si-LP (100 nm) showed good cycleability in the long-term cycle test, we found another serious problem. The Coulombic efficiency was initially low and gradually increased to 98% at the 9th cycle and to 99% at the 80th cycle. It did not reach 100% even at the 500th cycle (99.8%). This fact indicates that solvent decomposition (and SEI growth) slowly proceeds and does not stop even at the 500thcycle. It is therefore important to completely suppress the solvent decomposition, e.g. by a good additive, for use in practical lithium-ion cells. Acknowledgment:This work was supported by JST (ALCA), Japan. References: [1] M. Saito et al., Solid State Ionics, 225, 506 (2012).; [2] T. Okubo et al., Electrochemistry, 80(10), 720 (2012).; [3] M. Saito et al., Extended Abstracts of The 38thConference on Solid State Ionics in Japan, 1A02, Kyoto (2012).

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Pure Si thin flakes (Si Leaf Powder® (Si-LP)) of different thicknesses (50, 100, 200, 300 and 400 nm) were prepared, and their charge/discharge properties were investigated as anode materials for lithium ion batteries (LIBs). Thickness of the thin Si-LP (100 nm) changed reversibly during charging and discharging, while the expanded thickness upon charging was kept after fully discharged for the thick one (300 nm), indicating insufficient Li de-alloying at C/6 rate. The slower kinetics for the thicker Si-LPs was also confirmed by examination of the open circuit potential (OCP) and the rate capability. These suggested that Li atoms diffused easily within the thinner Si-LPs and the uniform Li distribution suppressed the physical stress due to the Li alloying and de-alloying, resulting a good cycleability. In addition, addition of vinylene carbonate (VC) in electrolyte reduced charge transfer resistance of the Li alloying/de-alloying reaction and much more improved the cycleability of Si-LPs.

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Pure Si platelets (Si-LP, thickness: 100 nm) and Ni layer-laminated Si platelets with different thicknesses (Si/Ni/Si-LP50 (50/50/50 nm) and Si/Ni/Si-LP30 (30/30/30 nm)) were prepared by a vapor deposition method, and their charge/discharge properties were investigated as alternative negative electrode materials to graphite for lithiumion batteries. The shape of thin platelet effectively relieved the stress during the alloying and de-alloying processes, and improved the charge/discharge cycleability as compared with a commercially available Si powder. In particular, the laminated platelet samples showed very good cycleability, probably because of a shorter diffusion length of Li+ ions in the Si layers and an improved mechanical strength by the presence of the Ni layer.